Immune tolerance refers to a state in which the immune system does not attack a substance that could be an antigen. Immune tolerance can occur in the form of “self-tolerance,” meaning that the immune response is not generally mounted against self-antigens, or “acquired tolerance,” which is induced even against non-self-antigens under certain administration conditions. With regard to non-self-antigens, active suppression by regulatory T cells is assumed to be involved. Diseases in which immune tolerance is required such as allergic disease and autoimmune disease can be perceived as phenomena in which immunological unresponsiveness to self or non-self is collapsed.
Dendritic cells are lineage marker-negative, MHC class II-positive antigen presenting cells having dendrites. Hematopoietic stem cells are differentiated into immature dendritic cells, and further into mature dendritic cells via the myeloid and lymphoid pathways. Dendritic cells are widely present in the peripheral non-lymphatic tissues and lymphatic tissues in a variety of subsets of different differentiation lineages and levels of maturity. In the steady state (non-inflammatory state), the majority of dendritic cells remain immature, and upon weak antigenic stimulation and antigen presentation that may provide costimulation, immature dendritic cells induce clonal deletion and inactivation of naive T cells, while inducing and amplifying various regulatory T cells having immunosuppressive capacity. In light of this, immature dendritic cells are assumed to play an important role in the maintenance of immunological homeostasis via induction of immune tolerance associated with these regulatory mechanisms controlling T cell function. Meanwhile, in an inflammatory state caused by the invasion of exogenous antigens such as bacteria, viruses, and foreign bodies, immature dendritic cells that have ingested these exogenous antigens are differentiated into mature dendritic cells by inflammatory stimulation. As the most potent antigen presenting cells, mature dendritic cells provide antigenic stimulation and costimulation to naive T cells to induce them to differentiate into antigen-specific effector T cells, thereby inducing immune response. Also, as antigen presenting cells exhibiting potent immune tolerance-inducing capacity even in an inflammatory state, regulatory dendritic cells (also referred to as tolerogenic dendritic cells in some cases) are known.
In regard to regulatory dendritic cells, a method for inducing human immunoregulatory dendritic cells by culturing human dendritic cells or precursor cells thereof with cytokines including at least IL-10 and TGF-β in vitro, human immunoregulatory dendritic cells obtained by the above method, and a pharmaceutical composition comprising the above human immunoregulatory dendritic cells (see Patent Document 1), a method of producing tolerogenic dendritic cells, including the step of incubating isolated dendritic cells with respiratory syncytial virus in an amount sufficient to infect the dendritic cells under conditions that trigger the cell surface expression of the following cell surface CD80high, CD86high, CD40high and CD83low (see Patent Document 2), and technology relevant to a preventive or therapeutic agent for diseases induced by excessive secretion of inflammatory cytokines (for example, sepsis), an IL-10 production promoting agent, an apoptosis inhibitory agent, and the like, all of which comprise regulatory dendritic cells (see Patent Document 3), are known.
ALA is known as an intermediate in tetrapyrrole biosynthesis pathways present in a wide range of animals, plants, or bacteria. This acid is commonly biosynthesized from succinyl CoA and glycine by 5-aminolevulinic acid synthase. Photodynamic therapy using ALA (hereinafter, also referred to as “ALA-PDT”) has also been developed and has received attention as a low invasive treatment method capable of maintaining QOL. For example, diagnostic or therapeutic agents for tumor comprising ALA and so on have been reported. In addition, ALA is also known to be useful as a preventing and improving agent or a therapeutic agent for adult disease, cancer, or male sterility (see e.g., Patent Documents 4 to 6).